Project summary: No effective therapeutic modalities exist for Alzheimer's disease (AD). ApoE4 allele is the number one genetic risk factor for AD increasing the risk 12-fold in homozygotes, but the mechanism for the increased risk was not known. Recent reports advocate that apoE4 has impaired cooperation with its lipidation protein the ATP Binding Cassette-A1 (ABCA1) resulting in insufficient loading from glial cells to the apoE4 acceptor particle. The apoE4 lipidation deficiency in turn is resulting in perturbed glial and neuron cell cholesterol homeostasis, A? accumulation, neuron degeneration and cognitive decline. Artery Therapeutics, Inc. (Artery) has focused more than 10 years on developing ABCA1 agonists, originally as therapeutics for atherosclerotic cardiovascular disease. ABCA1 promotes cholesterol removal and helps maintain macrophage (protective) phenotypes. This results in atherosclerosis plaque reduction and stabilization. CS6253 was developed in a screening program and refocusing of the ABCA1 agonist program to brain-penetrant therapeutics for apoE4 dementia including AD. CS6253 stabilizes ABCA1 and lowers the energy requirement for transferring cholesterol to apoE4 acceptor particles in a process involving oligomerization and cell membrane lipid rearrangement. CS6253 reduces A? plaque in 5x EFAD mice and prevents apoE4 driven AD pathogenesis including intra-neuronal A? in apoE4 TR mice. CS6253 is a drugable molecule with a unique set of brain and plasma biomarkers of importance in translation to primate studies. CS6253 treatment increases apoE receptor levels and reduces AD variables as A? and P-tau. CS6253 causes statistically significant reductions in plasma apoJ/CLU and neurofilament-light indicating neuroprotection and shows unique changes in plasma and brain apoE. Outside CNS CS6253 reduces atherosclerosis and shows anti-diabetic actions. The favorable vascular- metabolic properties of CS6253 may contribute to protective effects in AD and in apoE4 non-chronic conditions as traumatic brain injury, chemo-brain and vascular complications. We propose a phase 1 in which development feasibility is tested in non-GLP NHP studies (PK, maximum tolerated (single) dose, dose-range finding toxicology) with concomitant assessment of target engagement and other biomarkers. NHPs have more similar lipid metabolism and BBB properties to humans than rodents. Provided phase 1 results meet the pre-defined go/no-go criteria for development feasibility a phase 2 will ensue. Phase 2 includes an IND-enabling program with AD biomarker assessments to make CS6253 ready for clinical trials in humans with and without apoE4 providing biomarker proof of concept. Artery is a San Francisco based small business entity with patents licensed from LBNL, and ongoing collaborations under MTA with academic groups and pharma companies. Artery has the medical expertise, experience and drug-development network to successfully execute the suggested phase 1 and phase 2.